Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment

ABSTRACT

A compound for treating a patient having a solid tumor in which it is known or suspected that hypoxic cells are present, which is a compound of formula (A): ##STR1## wherein X represents a nitro-substituted aromatic or hetero-aromatic group with a one-electron reduction potential at pH 7 of from -250 to -500 mV; each of R&#39; 1  to R&#39; 5  independently represents hydrogen or an alkyl, hydroxyalkyl, aryl, aralkyl or alkaryl group; m is 0 or 1; n is 1 or 2; and Z&#39; represents a leaving group which has the potential for expulsion via an intramolecular cyclization reaction; or a physiologically acceptable acid addition salt thereof.

This invention relates to nitro-substituted aromatic and hetero-aromaticcompounds useful in cancer treatment. More particularly, it relates tosuch compounds useful in the treatment of cancer patients byradiotherapy or chemotherapy.

GB-A-2 123 816 is concerned with the nitroimidazoles of formula (I):##STR2## in which R₁ represents hydrogen or an alkyl group such C₁ -C₆alkyl; R₂ -R₅ represent hydrogen, alkyl such as C₁ -C₆ alkyl, aryl,aralkyl or alkaryl; and n is 1 or 2. These compounds are useful inincreasing the sensitivity of tumour cells to radiation in radiotherapyand also in potentiating or enhancing damage to tumours bychemotherapeutic agents. A variety of processes are disclosed for thepreparation of these compounds, including cyclising a compound offormula (VII): ##STR3## in which R₁ -R₅ and n are as defined above and Zrepresents halogen, typically bromine or chlorine. However, no specificcompounds with this formula are identified.

We have now found that compounds of formula (VII) can act asradiosensitisers and bioreductive agents in their own right, as mayanalogues of these compounds. They exhibit differential hypoxiccytotoxicity and may act as chemopotentiators. Accordingly, the presentinvention provides compounds for use in treating cancer, in particularfor treating a patient having a solid tumour in which it is known orsuspected that hypoxic cells are present, which have the formula (A):##STR4## wherein X represents a nitro-substituted aromatic orhetero-aromatic group with a one-electron reduction potential at pH 7(E₇ ¹ ; Wardman and Clarke, J Chem Soc Faraday Trans I 72 1377-1390(1976)) of from -250 to -500 mV; each of R'₁ to R'₅ independentlyrepresents hydrogen or an alkyl, hydroxyalkyl, aryl, aralkyl or alkarylgroup; m is 0 or 1; n is 1 or 2; and Z' represents a leaving group whichhas the potential for expulsion via an intramolecular cyclisationreaction; and physiologically acceptable acid addition salts thereof.

Certain classes of these compounds are novel. The invention thereforealso provides compounds of formula (B): ##STR5## wherein X, R'₁ to R'₅,m, n and Z' are as defined above with the proviso that m is 1 when Xrepresents ##STR6## in which R is hydrogen or an alkyl group, R'₁ ishydrogen, each of R'₂ to R'₅ independently represents hydrogen, alkyl,aryl, aralkyl or alkaryl and Z' represents halogen and when Xrepresents: ##STR7## each of R'₁ to R'₅ is hydrogen and Z' is ##STR8##and physiologically acceptable acid addition salts thereof.

Preferably Z' in formulae (A) and (B) is not a negatively-charged groupsuch as phosphate. Indeed, preferably the compounds of formulae (A) and(B) are not negatively-charged but are uncharged.

An alkyl group is typically a C₁ -C₆ group, preferably methyl. Ahydroxyalkyl group is typically a hydroxy (C₁ -C₆ alkyl) group such ashydroxymethyl. An aryl group is typically phenyl. An aralkyl group istypically a phenyl (C₁ -C₆) alkyl group such as benzyl. An alkaryl groupis typically a (C₁ -C₆) alkyl phenyl group such is methyl-substituted

Novel individual compounds are:

1-(2-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanol hydrochoride,

1-(2-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol hydrobromide,

1-(2-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanol hydriodide,

1-(2-nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanol hydrochoride,

1-(2-nitro-1-imidazolyl)-3-(2-acetoxyethylamino)-2-propanol,

1-(2-nitro-1-imidazolyl)-3-(2-trifluoroacetoxyethylamino)-2-propanol,

1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochoride,

1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide,

1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide,

1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochoride,

1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide,

1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide,

1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanolhydrochoride,

1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-chloroethylamino)-2-propanolhydrochoride,

1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-bromoethylamino)-2-propanolhydrobromide,

1-(2-nitro-1-imidazolyl)-3-(3-bromopropylamino)-2-propanol hydrobromide,

1-(2-nitro-1-imidazolyl)-3-(1-chloro-2-methyl-2-propylamino)-2-propanolhydrochloride,

1-(2-nitro-1-imidazolyl)-3-(1-bromo-2-methyl-2-propylamino)-2-propanolhydrobromide,

1-(2-nitro-1-imidazolyl)-3- (dl-threo-2-chloro-3-butylamino)-2-propanolhydrochloride,

1-(2-nitro-1-imidazolyl)-3-(dl-threo-2-bromo-3-butylamino)-2-propanolhydrobromide,

1-(2-nitro-1-imidazolyl)-3-(2-chloro-2,3-dimethyl-3-butylamino)-2-propanolhydrochloride, and

1-(2-nitro-1-imidazolyl)-3-(2-bromo-2,3-dimethyl-3-butylamino)-2-propanolhydrobromide.

Group X is a mononitro-substituted ring It may also be substituted by analkyl group, preferably a C₁ -C₆ alkyl group such as methyl. The ring ispreferably a 5- or 6-membered ring incorporating one, two or threenitrogen atoms in the ring. More preferred are the groups: ##STR9##wherein R is hydrogen or an alkyl group such as C₁ -C₆ alkyl. Preferrednovel classes of compounds are therefore compounds of formula (C) and(D): ##STR10## wherein R, R'₁ to R'₅, Z', m and n are as defined abovewith the proviso that m is 1 when R'₁ is hydrogen, each of R'₂ to R'₅independently represents hydrogen, alkyl, aryl, aralkyl or alkaryl andZ' represents halogen in formula (C), and physiologically acceptableacid addition salts thereof.

When R is alkyl, it is preferably a C₁ -C₆ alkyl group and morepreferably a methyl group. Preferred values for R are hydrogen andmethyl. The nitro group is preferably in the 2-position when Xrepresents an imidazol-1-yl group or in the 3-position when X representsa 1,2,4-triazol-1-yl group. The preferred value for m is 0 and for n is1.

R'₁ to R'₅ are each preferably independently hydrogen or C₁ -C₆ alkyl.The preferred alkyl group is methyl. Preferred are compounds in whichR'₁ is hydrogen and each of R'₂ to R'₅ is independently hydrogen ormethyl. Examples of such compounds are those in which R'₁ is hydrogenand R'₂ to R'₅ are each hydrogen or R'₂ to R'₃ are hydrogen and R'₄ andR'₅ are methyl or R'₂ and R'₄ are methyl and R'₃ and R'₅ are hydrogen orR'₂ and R'₃ are methyl and R'₄ and R'₅ are hydrogen or and R'₂ to R'₅are each methyl.

Z' represents a leaving-group function which has the potential forexpulsion via an intramolecular cyclisation reaction. For example, Z'may be halogen; --OCOR₆, --OSOR₆, --OSO₂ R₆, --OPO₃ (R₆)₂, or--OP(O)(N(R₆)₂)₂ where R₆ is hydrogen, alkyl, haloalkyl, aryl, aralkyl,thioalkyl, acyl or amino; or aryloxy, --ONO₂, --NHSO₂ R₇, --NHCOR₇,--NHCO₂ R₇, --N(COR₇)₂ or cyclic imide where R₇ is hydrogen, alkyl, arylor aralkyl; or --N⁺ R^(a) R^(b) R^(c) or --N(O)R^(a) R^(b) where R^(a)to R^(c) are independently alkyl or a N-heterocycle such as pyridine orimidazole.

From amongst these, Z' typically may be halogen or acyloxy unsubstitutedor substituted by halogen. Preferred are halogen, C₁ -C₆ alkanoyloxy andper- or poly-fluoro-C₂ -C₆ alkanoyloxy. More preferred are fluorine,chlorine, bromine, iodine, acetoxy and trifluoroacetoxy. Most preferredis bromine.

Acid addition salts of the compounds of formula (A) may be salts withany physiologically acceptable acid. Examples of suitable acids areinorganic acids such as hydrochloric, hydrobromic and hydriodic acid.Organic acids may be used. Preferred are hydrohalic acids in which thehalogen anion corresponds to the halogen denoted by the group Z',although this is not essential. Particularly preferred compounds are1-(2-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol and its saltsespecially the hydrobromide.

A variety of ways can be used to prepare a compound of formula (A). Acompound of formula (E):

    XCH.sub.2 (CHOH).sub.n CH.sub.2 N                          (E)

wherein X, m, n and R'₂ to R'₅ are as defined above, may be reacted witha compound of formula (F):

    HZ'                                                        (F)

wherein Z' is as defined above. Compounds of formula (A) in which R'₁ ishydrogen are thus prepared. Reaction is typically effected in thepresence or absence of an inert organic solvent. When an inert organicsolvent is used, this may suitably be a C₁ -C₄ alkanol (e.g. methanol orethanol), 2-propanone or other low-boiling alkanone,N,N-dimethylformamide or -acetamide, or the like. Alternatively, anexcess of the reagent of formula (F) may be used, either as the solventor as an aqueous solution. When water is employed as cosolvent or as thesolvent for one of the reagents, products due to hydrolysis of compound(E) are also formed. The reaction may be carried out at from 0° C. toroom temperature. The use of elevated temperatures may lead to partialpolymerisation, and hence lowered product yields. In a preferredprocedure, the reaction is carried out at a temperature of from 0 to 10°C. using 2-propanone as solvent and 2.0 or more mol equivalents ofcompound (F).

Another process for the preparation of compounds of formula (A) in whichZ' is halogen is via selective or partial halogenation of a compound offormula (G): ##STR11## wherein X, m, n and R'₁ to R'₅ are as definedabove and R₈ is hydrogen or an O-protecting function (e.g.2-tetrahydropyranyl ether or tert-butyldimethylsilyl ether), andsubsequent removal of the hydroxy protecting group, if present.Halogenation may be effected using a variety of conventionalhalogenating reagents. Treatment of a compound of formula (G) with, forexample, chlorotrimethylsilane and sodium iodide in acetonitrilesolution by a standard procedure (Synthesis 1979 379; J Org Chem 1979 441247) provides compounds of formula (A) where Z' is iodine. Analogoustreatment of compound (G) with bromotrimethylsilane using a literaturemethod (Tetrahed Letters 1978 4483) affords compounds of formula (A)where Z' is bromine. Reaction of the alcohol (G) withhexachloro-2-propanone and triphenylphosphine in sulpholane solutionusing a general method (see, e.g. J Org Chem 1981 46 824) givescompounds of formula (A) where Z' is chlorine.

In a preferred process, a compound of formula (G) is treated with astoichiometric quantity of dimethylbromosulphonium bromide inN,N-dimethylformamide solution at 50° C. to yield a compound of formula(A) in which Z' is bromine. In a second preferred process, a compound offormula (G) is heated to 50° C. with 1.5 mol equivalents each ofN-bromosuccinimide and triphenylphosphine in N,N-dimethylformamidesolution to give a compound of formula (A) in which Z is bromine.

Further, compounds of formula (A) can be prepared by reacting a compoundof formula (H) or (J): ##STR12## wherein X and n are as defined aboveand Q is typically chlorine or bromine, with a compound of formula (K):##STR13## wherein m, R'₁ to R'₅ and Z' are as defined above, or an acidaddition salt thereof. The reaction is typically effected in thepresence or absence of an inert organic solvent. When an inert organicsolvent is used, this may suitably be a C₁ -C₄ alkanol (e.g. methanol orethanol), N,N-dimethylformamide or -acetamide, or similar. Reactionsinvolving condensation of compounds (J) and (K) may be accelerated bythe use of 1 mol equivalent of an acid-binding agent such as analkali-metal carbonate (e.g. sodium or potassium carbonate) or atertiary organic amine (e.g. pyridine or triethylamine). The use of 2mol equivalents of compound (K) is preferred in such a reaction. Thereaction may be carried out at room temperature or at an elevatedtemperature. In a preferred process, the reaction is carried out inethanol solution at reflux temperature, without using an acid-bindingagent.

In another procedure, a compound of formula (L):

    X--H                                                       (L)

or its metal salt derivative (e.g. X⁻ Na⁺), where X is as defined above,may be reacted with a compound of formula (M): ##STR14## or,alternatively, with a compound of formula (N): ##STR15## where m, n, R'₁to R'₅, Q and Z' are as defined above. The reaction is typicallyeffected in the presence or absence of an inert organic solvent. When aninert organic solvent is employed, this may suitably be a C₁ -C₄ alkanol(e.g. methanol or ethanol), N,N-dimethylformamide or -acetamide, orsimilar. Reactions between compounds of formula (L) and (N) may beaccelerated by the use of 1 mol of an added acid-binding agent, asdiscussed above. The use of 2 mol equivalents of the amine-compound (N)is to be preferred. Either reaction may be carried out at roomtemperature or at elevated temperatures, up to the boiling point of thesolvent. In a preferred process, the sodio- or lithio-salt of a compoundof formula (L) is condensed with an equimolar quantity of either (M) or(N) in methanol or N,N-dimethylformamide solution at 50° C.

In a further process, a compound of formula (O): ##STR16## is convertedto a compound of formula (P): ##STR17## wherein m, n, R'₁ to R'₅, X andZ' are as defined above. This is typically achieved via N-alkylation orN-arylation by treatment with, for example, (i) a haloalkane (e.g.iodomethane, etc), haloalkylarene or haloarene at room temperature usingeither acetone or excess reagent as solvent (i.e. R'₁ =alkyl, aralkyl oraryl); (ii) oxirane using the reagent as solvent or, alternatively, inmethanol or ethanoic acid solution at 0-30° C. (i.e. R'₁ =--CH₂ CH₂ OH);(iii) methanal/acetophenone (or other compound containing an activehydrogen atom) by Mannich condensation using a conventional procedure(i.e. R'₁ =--CH₂ CH₂ COC₆ H₅, or similar); (iv) methanal/sodiumcyanotrihydridoborate by reductive alkylation using a standard procedure(see e.g. Aldrichimica Acta 1979 12(2) 34) (i.e. R'₁ =--CH₃).

Yet further compounds of formula (A) in which m is 1 and O respectivelyand Z' is halogen can be prepared by conversion of an unsaturatedcompound of formula (S):

    X--CH.sub.2 (CHOH).sub.n CH.sub.2 NR'.sub.1 CR'.sub.2 R'.sub.3 CH═CR'.sub.4 R'.sub.5                                 (S)

or a compound of formula (T):

    X--CH.sub.2 (CHOH).sub.n CH.sub.2 NR'.sub.1 CR'.sub.2 ═CR'.sub.4 R'.sub.5                                                  (T)

where X, n and R'₁ to R'₅ are as defined above. In a general procedure(J Org Chem 1981 46 2582, 3113; Synth Comm 1981 11 521), a compound offormula (S) or (T) is first reacted with di(cyclohexyl)borane andsubsequently treated with chloramine-T, bromine or iodine monochlorideto give a compound of formula (A) where Z is chlorine, bromine oriodine, respectively.

The compounds of formula (A) may be converted as desired into aphysiologically acceptable acid addition salt thereof. Preferably, thecompounds are isolated as such from the reaction mixture.

The compounds of formula (A) and their salts are useful in increasingthe sensitivity of tumour cells to radiation in radiotherapy and asbioreductive agents. A compound is administered to a patient having aradiation treatable cancer, prior to or shortly after irradiation of thetumour, in an amount effective to increase the sensitivity of the tumourcells to the effects of the irradiation.

Any solid tumour, which may have regions where cells areradiobiologically hypoxic and become resistant to ionising radiation,may be treated. Examples of such tumours are epithelial tumours of thehead, neck, thorax and abdomen, soft tissue sarcomas and brain tumours.The compounds of formula (A) and their salts can therefore be employedin the radiotherapy of all such solid tumours where hypoxic cells areknown or suspected to exist.

The compounds of formula (A) and their salts may also be used where anagent having differential hypoxic cytotoxicity is required. Thecompounds can be employed for chemopotentiation of a chemotherapeuticagent or as a chemotherapeutic by administration of a compound (A) orsalt thereof to a patient having a localised or metastatic cancer.Administration is generally carried out prior to simultaneously with orafter administration of a chemotherapeutic agent such as melphalan,cyclophosphamide, 5-fluorouracil, adriamycin orCCNU(1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea). Any solid tumours,such as above, which are primary or secondary deposits, where it isknown or suspected that hypoxic cells are present can therefore benefitfrom treatment employing a compound of formula (A) or salt thereof.

The compounds of formula (A) and salts thereof may be administeredorally or intravenously. The amount administered depends on factors suchas the cancer, the condition of the patient and the body weight of thepatient. Typically, however, doses of 50 to 1000 mg/m² of a patient'sbody area may be employed.

A compound of formula (A) or a physiologically acceptable salt thereofmay be formulated in a manner appropriate to the treatment for which itis to be used by bringing it into association with a pharmaceuticallycompatible carrier or diluent. The compound may be included in a dosageform such as a tablet or capsule, for example a capsule comprising knownformulation components such as one or more of those described in ExampleA of GB-A-2 003 154. The compound may also be formulated for intravenousadministration e.g. in a saline drip solution.

The invention therefore also provides a pharmaceutical compositioncomprising a compound of formula (A) or a physiologically acceptablesalt thereof and a pharmaceutically compatible carrier or diluent. Thecomposition must be sterile and pyrogen-free. It may be presented inunit dosage form.

The following Examples illustrate the invention.

EXAMPLE 1 1-(2-Nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanol(RB-6144)

(a) A mixture containing1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol (RSU-1069) preparedby the method of Adams et al. [Adams, G.E., Ahmed, I., Gibson, D. andStratford, I.J., GB-A-2123816] (2.12 g, 10.0 mmol) and purified byrecrystallisation [O'Neill, P., McNeil, S.S. and Jenkins, T.C.,Biochemical Pharmacology 1987 36 1787-1792] and acetone (20 cm³) waswarmed to 40° C. The resulting clear solution was cooled with stirringto 5°-10° C. using an external ice-water bath and treated with asaturated solution of hydrogen chloride in acetone (20 cm³). Anexothermic reaction ensued. The reaction mixture was treated withdecolourising charcoal (0.3 g), filtered whilst still w arm and allowedto crystallise to give1-(2-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanol hydrochloride(2.66 g, 93%) as a very pale yellow crystalline solid, m.p. 153°-154° C.(dec.). Recrystallisation from aqueous acetone afforded pale yellowprisms of unchanged melting point, after drying in vacuo (P₂ O₅, 0.1Torr, 25° C. for 72 hours).

Infra-red (KBr, cm-¹): 3450(br.sh., NH₂ ⁺),3345(br.,OH),3146+3090(imid.C-H),3030,3010,2975,2945,2880,2845,2770,2680,2620,2560,2510,2420,1593,1542,1509,1495,etc.

Analysis for C₈ H₁₄ N₄ O₃ Cl₂ (M=285.13):

Calculated: C: 33.70; H: 4.95; N: 19.65; Cl: 24.87%,

Found: C: 33.91; H: 5.02; N: 19.64; Cl: 24.63%.

(b) A solution of1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol(2.12 g, 10.0 mmol)in acetone (20 cm³) red as described in Example 1(a) was stirred at 0-5°C. using external ice-water cooling. Concentrated aqueous hydrochloricacid (38% w/w HCl, 2.0 cm³) was added in one portion. The mixture wastreated with decolourising charcoal (0.3 g), filtered and chilled togive 1-(2-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride (1.89 g, 66.3%) as a pale yellow microcrystalline solid,m.p. 152.5°-153.5° C. (dec.) after drying in vacuo.

EXAMPLE 2 1-(2-Nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol(RB-6145)

(a) In a manner analogous to that described in Example 1 (a) there wasobtained by condensation of1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol with anhydroushydrogen bromide,1-(2-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol hydrobromidein the form of a very pale yellow crystalline solid, m.p. 150.5°-151.5°C. (dec.); yield 96%.

Infra-red (KBr, cm⁻¹): 3450(br.sh.,NH₂⁺),3345(br.,OH),3160+3140+3087(imid.C--H),3045,3010,2975,2940,2930,2900,2835,2775,2760,2678,2640,2600,2540,2500,2418,1590,1539,1507, 1493,etc.

Analysis for C₈ H₁₄ N₄ O₃ Br₂ (M=374.05):

Calculated: C: 25.69; H: 3.77; N: 14.98; Br: 42.73%,

Found: C: 25.82; H: 3.80; N: 15.15; Br: 42.49%.

(b) In a manner analogous to that described in Example 1(b) there wasobtained by reaction of1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol with a small excessof aqueous hydrobromic acid (48% w/w HBr) at 0°-5° C. andrecrystallisation from aqueous acetone,1-(2-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol hydrobromideas a pale yellow crystalline solid, m.p. 150°-151° C. (dec.) afterdrying in vacuo for 72 hours; yield 59%.

(c) A mixture containing1-(2-nitro-1-imidazolyl)-3-(2-hydroxyethylamino)-2-propanol (RSU-1137)prepared as described by Silver et al. [Silver, A.R.J., McNeil, S.S.,O'Neill, P., Jenkins, T.C. and Ahmed, I., Biochemical Pharmacology 198635 3923-3928] (2.30 g, 10.0 mmol) and dimethylbromo-sulphonium bromide(2.22 g, 10.0 mmol) prepared by the method of Furukawa et al. [Furukawa,N., Inoue, T., Aida, T. and Oae, S., J. Chem. Soc. Chem. Commun. 1973212] in N,N-dimethylformamide (20 cm³) was stirred at 50° C. for 12hours. The reaction mixture was concentrated in vacuo, digested inethanol (10 cm³) and separated by preparative column chromatographyusing silica gel as the stationary phase and chloroform-methanol (9:1v/v) as eluant.1-(2-Nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol hydrobromide(0.68 g, 18.2%) was obtained as a yellow solid, m.p. 148.5°-150.5° C.after treatment of the eluate with ethereal hydrogen bromide.

EXAMPLE 3 1-(2-Nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanol(RB-6146)

In a manner analogous to that described in Example 1(b) there wasobtained by reaction of1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol with aqueoushydriodic acid (57% w/w HI) at 0°-5° C. and recrystallisation fromwater, 1-(2-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide as a yellow microcrystalline solid, m.p. 172°-173° C. (dec.)after drying in vacuo; yield 51%.

Analysis for C₈ H₁₄ N₄ O₃ I₂ (M=468.04):

Calculated: C: 20.53; H: 3.02; N: 11.97; I: 54.23%,

Found: C: 21.02; H: 3.11; N: 12.12; I: 53.26%.

EXAMPLE 4 1-(2-Nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanol(RB-6159)

(a) A mixture of 1-(2,3-epoxypropyl)-2-nitroimidazole prepared by themethod described by Beaman et al. [Beaman, A.G., Tautz, W. andDuschinsky, R., 1968; Studies in the Nitroimidazole Series. III,Antimicrobial Agents and Chemotherapy, pp. 520-530] (4.00 g, 23.7 mmol),2-fluoro-ethylammonium chloride (5.00 g, 50.2 mmol) and sodium hydroxide(2.00 g, 50.0 mmol) in ethanol (60 cm³) was stirred at 15° C. for 30minutes then heated under reflux for 3 hours. The reaction mixture wasthen treated with decolourising charcoal (0.5 g), cooled and filtered.Concentration under reduced pressure afforded a pale yellow oil whichwas dissolved in ethanol (20 cm³) and treated with a small excess ofanhydrous ethereal hydrogen chloride to give1-(2-nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanol hydrochloridein the form of a pale yellow crystalline solid (4.38 g, 68.9%) afterrecrystallisation from aqueous ethanol, m.p. 178°-179° C. (dec. afterdrying in vacuo.

Analysis for C₈ H₁₄ N₄ O₃ FCl (M=268.67):

Calculated: C: 35.76; H: 5.25; N: 20.85; F: 7.07; Cl: 13.20%,

Found: C: 35.41; H: 5.17; N: 20.65; F: 6.90; Cl: 13.38%.

(b) In a manner analogous to that described in Example 1(b) there wasobtained by reaction of1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol with aqueoushydrofluoric acid (48% w/w HF) at 0°-5° C.,1-(2-nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanol hydrochlorideafter stirring with cold ethanolic sodium hydroxide (1.0 mol equivalent)and decolourising charcoal for 15 minutes, filtration and treatment witha small excess of ethereal hydrogen chloride; yield 41%, m.p. 177°-179°C. (dec.).

EXAMPLE 5 1-(2-Nitro-1-imidazolyl)-3-(2-acetoxyethylamino)-2-propanol

A solution of 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol (2.12g, 10.0 mmol) in acetone (20 cm³) prepared as described in Example 1(a)was treated with ethanoic acid (2.5 mol equivalents) at 25° C. thenwarmed to 50° C. for 15 minutes. The resulting mixture was cooled to 20°C., stirred with decolourising charcoal (0.3 g) and excess anhydrouspotassium carbonate for 30 minutes, filtered and concentrated underreduced pressure to give1-(2-nitro-1-imidazolyl)-3-(2-acetoxyethylamino)-2-propanol (1.58 g,58.0%) in the form of a pale yellow crystalline solid.

EXAMPLE 61-(2-Nitro-1-imidazolyl)-3-(2-trifluoroacetoxyethylamino)-2-propanol

In a manner analogous to that described in example 5 there was obtainedfrom reaction of 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanolwith trifluoroethanoic acid,1-(2-nitro-1-imidazolyl)-3-(2-trifluoroacetoxyethylamino)-2-propanol asa yellow oil; yield 43%.

EXAMPLE 71-(2-Methyl-4-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanol

In a manner analogous to that described in Example 1(b) there wasobtained by condensation of1-(2-methyl-4-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol [Adams,G.E., Ahmed, I., Gibson, D. and Stratford, I.J., GB-A-2123816; Ahmed,I., Jenkins, T.C., Walling, J.M., Stratford, I.J., Sheldon, P.W., Adams,G.E. and Fielden, E.M., Int. J. Radiat. Oncol. Biol. Phys. 1986 121079-1081] with aqueous hydrochloric acid at 0-5° C.,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride as very pale yellow prisms, after recrystallisation fromethanol and drying in vacuo; yield 67%.

Analysis for C₉ H₁₆ N₄ O₃ Cl₂ (M=299.16):

Calculated: C: 36.13; H: 5.39; N: 18.73; Cl: 23.70%,

Found: C: 35.89; H: 5.47; N: 18.86; Cl: 24.04%.

EXAMPLE 81-(2-Methyl-4-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol

In a manner analogous to that described in Example 2(b) there wasobtained by reaction of1-(2-methyl-4-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol with excessaqueous hydrobromic acid at 0°-5° C.,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide as a cream-coloured microcrystalline solid; yield 45%.

EXAMPLE 91-(2-Methyl-4-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanol

In a manner analogous to that described in example 3 there was obtainedby condensation of1-(2-methyl-4-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol withaqueous hydriodic acid,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide as a yellow crystalline solid; yield 52%.

EXAMPLE 101-(2-Methyl-5-nitro-1-imidazolyl)-3-(2-halo-ethylamino-2-propanol:(halo=Cl,Br, I or F)

These compounds are preparable as the acid salts by reaction of1-(2-methyl-5-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol prepared bythe method of Adams et al. [Adams, G.E., Ahmed, I., Gibson, D. andStratford, I.J., GB-A-2123816; Ahmed, I., Jenkins, T.C., Walling, J.M.,Stratford, I.J., Sheldon, P.W., Adams, G.E. and

Phys. 1986 12 Fielden, E.M., Int. J. Radiat. Oncol. Biol. Phys. 1986 121079-1081] with the appropriate aqueous hydrohalic acid or anhydroushydrogen halide in either acetone or ethanol solution at 0-5° C.,following the procedures described in Examples 1-4, by analogy with theprocesses described in Examples 8 to 10.

EXAMPLE 111-(3-Nitro-1,2,4-triazol-1-yl)-3-(2-chloroethylamino)-2-propanol

In a manner analogous to that described in Example 1(b) there wasobtained by treatment of1-(3-nitro-1,2,4-triazol-1-yl)-3-(1-aziridino)-2-propanol [Shibamoto,Y., Sakano, K., Kimura, R., Nishidai, T., Nishimoto, S.-I., Ono, K.,Kagiya, T. and Abe, M. Int. J. Radiat. Oncol. Biol. Phys. 1986 121063-1066] with aqueous hydrochloric acid at 25° C.,1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-chloroethylamino)-2-propanolhydrochloride as colourless prisms, m.p. 179-180° C.; yield 85%.

Analysis for C₇ H₁₃ N₅ O₃ Cl₂ (M=286.12):

Calculated: C: 29.39; H: 4.58; N: 24.48; Cl: 24.78%,

Found: C: 29.62; H: 4.83; N: 24.74; Cl: 24.18%.

EXAMPLE 121-(3-Nitro-1,2,4-triazol-1-yl)-3-(2-bromoethylamino)-2-propanol

In a manner analogous to that described in Example 2(b) there wasobtained by reaction of1-(3-nitro-1,2,4-triazol-1-yl)-3-(1-aziridino)-2-propanol with aqueoushydrobromic acid,1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-bromoethylamino)-2-propanolhydrobromide in the form of hygroscopic colourless prisms, m.p.128°-129° C.; yield 63%.

Analysis for C₇ H₁₃ N₅ O₃ Br₂ (M=375.03):

Calculated: C: 22.42; H: 3.49; N: 18.67; Br: 42.61%,

Found: C: 22.59; H: 3.52; N: 19.08; Br: 42.06%.

EXAMPLE 13 1-(2-Nitro-1-imidazolyl)-3-(3-bromopropylamino)-2-propanol

A solution containing 3-bromopropylammonium bromide (6.47 g, 29.6 mmol)and sodium hydroxide (1.18 g, 29.5 mmol) in ethanol (40 cm³) was stirredat 20° C.; after 1 hour, diethyl ether (40 cm³) was added and themixture filtered. 1-(2,3-epoxypropyl)-2-nitroimidazole (5.00 g, 29.6mmol) was added to the filtrate and the solution heated to reflux for 45minutes. The reaction mixture was then treated with decolourisingcharcoal (0.5 g), filtered, concentrated under reduced pressure andtreated with aqueous hydrobromic acid (48% w/w HBr, 2.0 cm³). The solidwhich appeared upon refrigeration was recrystallised from aqueousethanol to give1-(2-nitro-1-imidazolyl)-3-(3-bromopropylamino)-2-propanol hydrobromide(6.87 g, 59.9%) as a hygroscopic yellow crystalline solid.

EXAMPLE 141-(2-Nitro-1-imidazolyl)-3-(1-chloro-2-methyl-2-propylamino)-2-propanol

In a manner analogous to that described in Example 1(b) there wasobtained following condensation of1-(2-nitro-1-imidazolyl)-3-(2,2-dimethyl-1-aziridino)-2-propanolprepared by the method described by Adams et al. [Adams, G.E., Ahmed,I., Gibson, D. and Stratford, I.J., GB-A-2123816] with aqueoushydrochloric acid at 40° C.,1-(2-nitro-1-imidazolyl)-3-(1-chloro-2-methyl-2-propylamino)-2-propanolhydrochloride as colourless prisms, m.p. 196.5°-198° C. (dec.) afterrecrystallisation from aqueous acetone containing 0.5% v/v aqueoushydrochloric acid; yield 78%.

Analysis for C₁₀ H₁₈ N₄ O₃ Cl₂ (M=313.19):

Calculated: C: 38.35; H: 5.79; N: 17.89; Cl: 22.64%,

Found: C: 38.24; H: 5.85; N: 17.82; Cl: 22.41%.

EXAMPLE 151-(2-Nitro-1-imidazolyl)-3-(1-bromo-2-methyl-2-propylamino)-2-propanol

In a manner analogous to that described in Example 2(b) there wasobtained from reaction of1-(2-nitro-1-imidazolyl)-3-(2,2-dimethyl-1-aziridino)-2-propanol withaqueous hydrobromic acid at 40° C.,1-(2-nitro-1-imidazolyl)-3-(1-bromo-2-methyl-2-propylamino)-2-propanolhydrobromide as very pale yellow prisms, m.p. 186°-187° C. (dec.); yield82%

Analysis for C₁₀ H₁₈ N₄ O₃ Br₂ (M=402.10):

Calculated: C: 29.87; H: 4.51; N: 13.93; Br: 39.75%,

Found: C: 29.92; H: 4.58; N: 13.91; Br: 39.23%.

EXAMPLE 161-(2-Nitro-1-imidazolyl)-3-(dl-threo-2-chloro-3-butylamino)-2-propanol

In a manner analogous to that described in Example 1(b) there wasobtained by condensation of1-(2-nitro-1-imidazolyl)-3-(cis-2,3-dimethyl-1-aziridino)-2-propanolprepared by the method described by Adams et al. [Adams, G.E., Ahmed,I., Gibson, D. and Stratford, I.J., GB-A-2123816] with aqueoushydrochloric acid at 20° C., 1-(2-nitro-1-imidazolyl)-3- (dl-threo-2-chloro-3-butylamino)-2-propanol hydrochloride as colourless prisms,m.p. 138.5°-139° C. (dec.) after recrystallisation from ethanol; yield73%.

EXAMPLE 171-(2-Nitro-1-imidazolyl)-3-(dl-threo-2-bromo-3-butylamino)-2-propanol

In a manner analogous to that described in Example 2(b) there wasobtained by reaction of1-(2-nitro-1-imidazolyl)-3-(cis-2,3-dimethyl-1-aziridino)-2-propanolwith aqueous hydrobromic acid at 20° C.,1-(2-nitro-1-imidazolyl)-3-(dl-threo-2-bromo-3-butylamino)-2-propanolhydrobromide as pale yellow prisms, m.p. 143°-144° C. (dec.); yield 78%.

EXAMPLE 181-(2-Nitro-1-imidazolyl)-3-(2-chloro-2,3-dimethyl-3-butylamino)-2-propanol

In a manner analogous to that described in Example 1(b) there wasobtained by reaction of1-(2-nitro-1-imidazolyl)-3-(2,2,3,3-tetramethyl-1-aziridino)-2-propanolsynthesised by the general method outlined by Ahmed et al. [Ahmed, I.,Jenkins, T.C., Walling, J.M., Stratford, I.J., Sheldon, P.W., Adams,G.E. and Fielden, E.M., Int. J. Radiat. Oncol. Biol. Phys. 1986 121079-1081] with excess aqueous hydrochloric acid at 20° C.,1-(2-nitro-1-imidazolyl)-3-(2-chloro-2,3-dimethyl-3-butylamino)-2-propanolhydrochloride as a colourless microcrystalline solid, m.p. 183°-184° C.(dec.) after recrystallisation from aqueous acetone; yield 61%.

EXAMPLE 191-(2-Nitro-1-imidazolyl)-3-(2-bromo-2,3-dimethyl-3-butylamino)-2-propanol

In a manner analogous to that described in Example 2(b) there wasobtained following condensation of1-(2-nitro-1-imidazolyl)-3-(2,2,3,3-tetramethyl-1-aziridino)-2-propanolwith aqueous hydrobromic acid,1-(2-nitro-1-imidazolyl)-3-(2-bromo-2,3-dimethyl-3-butylamino)-2-propanolhydrobromide as pale yellow prisms, m.p. 163°-164° C. (dec.) afterevaporation to low volume and recrystallisation from aqueous acetone;yield 56%.

Analysis for C₁₂ H₂₂ N₄ O₃ Br₂ (M=430.15):

Calculated: C: 33.51; H: 5.16; N: 13.03; Br: 37.15%,

Found: C: 33.80; H: 5.28; N: 12.79; Br: 36.83%.

EXAMPLE 201-(2-Nitro-1-imidazolyl)-3-(1-bromo-2-methyl-2-propylamino)-2-propanol

(a) In a manner analogous to the method described by Silver et al.[Silver. A.R.J., McNeil, S.S., O'Neill, P., Jenkins, T.C. and Ahmed, I.,Biochemical Pharmacology 1986 35 3923-3928],1-(2-nitro-1-imidazolyl)-3-(1-hydroxy-2-methyl-2-propylamino)-2-propanolwas obtained as very pale yellow prisms, m.p. 114.5°-115.5° C. afterrecrystallisation from ethanol; yield 81%.

(b) A mixture containing the alcohol prepared as described in (a) above(2.58 g, 10.0 mmol), N-bromosuccinimide (2.67 g, 15.0 mmol) andtriphenylphosphine (3.93 g, 15.0 mmol) in N,N-dimethylformamide (50 cm³)was stirred at 50° C. for 1.5 hours. The reaction mixture was thenconcentrated under reduced pressure, digested in ethanol (20 cm³),filtered and separated by preparative column chromatography using silicagel as the stationary phase and chloroform-methanol (9:1 v/v) as eluant.1-(2-Nitro-1-imidazolyl)-3-(1-bromo-2-methyl-2-propylamino)-2-propanolhydrobromide was obtained as a yellow crystalline solid (1.09 g, 27.1%),m.p. 181°-184° C. (dec) after treatment of the eluate with a smallexcess of ethereal hydrogen bromide.

EXAMPLE 21 Sensitisation and Toxicity

(a) C3H mice in which the KHT tumour had been implanted subcutaneouslywere administered RB-6145 (Example 2) intraperitoneally before treatmentwith radiation. The time before such treatment at which the drug wasadministered was such that maximum enhancement was effected. The resultsof such treatment are set out in Table 1 with comparison to misonidazole(MISO), etanidazole (SR 2508) and pimonidazole (Ro 03-8799). In Table 2comparison is made with1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol (RSU-1069). Allcompounds were administered in phosphate buffered saline (PBS) at pH 7.4except RB-6145 which was administered in PBS at pH 5.4.

                                      TABLE 1                                     __________________________________________________________________________    Survival of KHT tumour cells following treatment with                         sensitiser at a dose of 200 mg/kg and 10 Gy X-rays                                      NONE MISO  SR 2508                                                                             Ro03-8799                                                                           RB-6145                                      __________________________________________________________________________    surviving fraction                                                                      3 × 10.sup.-2                                                                1.2 × 10.sup.-2                                                               1.1 × 10.sup.-2                                                               3 × 10.sup.-2                                                                 1.8 × 10.sup.-3                        enhancement ratio                                                                       1.0  1.5   1.6   1.0   2.7                                          __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Survival of KHT tumour cells following treatment with                         sensitiser and 10 Gy X-rays                                                   RB-6145 (Example 2)                                                                            RSU-1069                                                     Dose                 Dose                                                     mmol           surviving mmol          surviving                              kg.sup.-1                                                                           (mg/kg)  fraction  kg.sup.-1                                                                            (mg/kg)                                                                              fraction                               ______________________________________                                        0.80  300      1.4 × 10.sup.-3                                                                   0.38   80     1.6 × 10.sup.-3                  0.53  200      1.8 × 10.sup.-3                                                                   0.26   50     3.2 × 10.sup.-3                  0.27  100      5.2 × 10.sup.-3                                                                   0.14   30     4.0 × 10.sup.-3                  0.13  50       7.6 × 10.sup.-3                                                                   0.04   8      7.6 × 10.sup.-3                  ______________________________________                                    

The surviving fraction for 10 Gy alone is 3×10⁻². The maximum does usedwas the maximum tolerated dose (MTD). Much higher doses of RB-6145 canbe used but on a dose-for-dose basis it is the same as RSU-1069 as asensitiser.

(b) Sensitisation and toxicity data for some of the compounds describedin the above Examples are given in Table 3. ##STR18##

                  TABLE 3                                                         ______________________________________                                                                    C.sub.Air.sup.(a) /                                                                   C.sub.N.sbsb.2.sub.(a) /                  EXAMPLE   Compound  Z'      mmol dm.sup.-3                                                                        mmol dm.sup.-3                            ______________________________________                                        --        RSU-1137  OH      70      3.5                                       4         RB-6159   F       35      2.5                                       1         RB-6144   Cl      5       0.35                                      2         RB-6145   Br      2.3     0.09                                      3         RB-6146   I       2.4     0.08                                      ______________________________________                                                           .sup.(b) C.sub.1.6 /                                       EXAMPLE  C.sub.Air /C.sub.N.sbsb.2                                                               mmol dm.sup.-3                                                                          .sup.(c) in vivo sensitisation                   ______________________________________                                        --       20        0.45      ++                                               4        14        ND        ND                                               1        15        0.25      ++                                               2        25        0.15      ++++                                             3        30        0.3       ND                                               ______________________________________                                         .sup.(a) Toxicity is 3 hours at 37° C. Concentrations are those        required for a surviving fraction of 10.sup.-1. Drugs were made up in ful     growth medium (buffered with bicarbonate) just before addition to cells.      .sup.(b) Drugs made up in PBS at pH 7.4 just before addition to cells.        .sup.(c) Scoring system:                                                      ++++ equal or greater efficiency than RSU1069                                 +++ less than RSU1069 but greater than MISO                                   ++ equal to MISO                                                              + less than MISO                                                              ND = not determined.                                                     

We claim:
 1. A compound of formula (B): ##STR19## wherein is one of thegroups ##STR20## wherein R is hydrogen or an alkyl group, with aone-electron reduction potential at pH 7 of from -250 to -500 mV;each ofR'₁ to R'₅ independently represents hydrogen or an alkyl, hydroxyalkyl,aryl, aralkyl or alkaryl group; m is 0 or 1; n is 1 or 2; and Z'represents a leaving group which has the potential for expulsion via anintramolecular cyclization reaction and which is selected from the groupconsisting of halogen; --OCOR₆, --OSOR₆, --OSO₂ R₆, OPO₃ (R₆)₂ or--OP(O) (N(R₆)₂)₂ where R₆ is hydrogen, alkyl, haloalkyl, phenyl,aralkyl, thioalkyl, acyl or amino; aryloxy, --ONO₂, --NHSO₂ R₇,--NHCOR₇, --NHCO₂ R₇, --N(COR₇)₂ or cyclic imide where R₇ is hydrogen,alkyl, phenyl or aralkyl; and --N⁺ R^(a) R^(b) R^(c) or --N(O)R^(a)R^(b) where R^(a) to R^(c) are independently alkyl; or a physiologicallyacceptable acid addition salt thereof; with the proviso that m is 1where X represents ##STR21## in which R is hydrogen or an alkyl group,R'₁ is hydrogen, each of R'₂ to R'₅ independently represents hydrogen,alkyl, aryl, aralkyl or alkaryl and Z' represents halogen.
 2. A compoundaccording to claim 1, wherein X represents an imidazol-1-yl group havinga nitro group in the 2-position or a 1,2,4-triazol-1-yl group having anitro group in the 3-position.
 3. A compound according to claim 1,wherein m is
 0. 4. A compound according to claim 1, wherein n is
 1. 5. Acompound according to claim 1, wherein each of R'₁ to R'₅ independentlyrepresents hydrogen or C₁ -C₆ alkyl.
 6. A compound according to claim 5,wherein R'₁ is hydrogen and each of R'₂ and R'₅ is independentlyhydrogen or methyl.
 7. A compound according to claim 1, wherein Z' is ahalogen or acyloxy unsubstituted or substituted by a halogen.
 8. Acompound according to claim 1, which is in the form of a salt withhydrochloric, hydrobromic or hydriodic acid.
 9. A compound according toclaim 1, which is selected from the group consistingof:1-(2-nitro-1-imidazolyl)-3-(2-acetoxyethylamino)-2-propanol,1-(2-nitro-1-imidazolyl)-3-(2-trifluoroacetoxyethylamino)-2-propanol,1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-chloroethylamino)-2-propanolhydrochloride,1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-bromoethylamino)-2-propanolhydrobromide, and1-(2-nitro-1-imidazolyl)-3-(3-bromopropylamino)-2-propanol hyrobromide.10. A compound selected from the group consistingof:1-(2-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride, 1-(2-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide, 1-(2-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide, 1-(2-nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanolhydrochloride,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide,1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride,1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide,1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide,1-(2-methyl-5-nitro-1-imidzolyl)-3-(2-fluoroethylamino)-2-propanolhydrochloride,1-(2-nitro-1-imidazolyl)-3-(1-chloro-2-methyl-2-propylamino)-2-propanolhydrochloride,1-(2-nitro-1-imidazolyl)-3-(1-bromo-2-methyl-2-propylamino)-2-propanolhydrobromide,1-(2-nitro-1-imidazolyl)-3-(d1-threo-2-chloro-3-butylamino)-2-propanolhydrochloride,1-(2-nitro-1-imidazolyl)-3-(d1-threo-2-bromo-3-butylamino)-2-propanolhydrobromide,1-(2-nitro-1-imidazolyl)-3-(2-chloro-2,3-dimethyl-3-butylamino)-2-propanolhydrochloride, and1-(2-nitro-1-imidazolyl)-3-(2-bromo-2,3-dimethyl-3-butylamino)-2-propanolhydrobromide.
 11. A pharmaceutical composition comprising apharmaceutically compatible carrier or diluent and, as activeingredient, a compound of formula (A): ##STR22## wherein X is one of thegroups ##STR23## wherein R is hydrogen or an alkyl group, with aone-electron reduction potential at pH 7 of from -250 to -500 mV;each ofR'₁ to R'₅ independently represents hydrogen or an alkyl, hydroxyalkyl,aryl, aralkyl or alkaryl group; m is 0 or 1; n is 1 or 2; and Z'represents a leaving group which has the potential for expulsion via anintramolecular cyclization reaction and which is selected from the groupconsisting of halogen; --OCOR₆, --OSOR₆, --OSO₂ R₆, --OPO₃ (R₆)₂ or--OP(O)(N(R₆)₂)₂ where R₆ is hydrogen, alkyl, haloalkyl, phenyl,aralkyl, thioalkyl, acyl or amino; aryloxy, --ONO₂, --NHSO₂ R₇,--NHCOR₇, --NHCO₂ R₇, --N(COR₇)₂ or cyclic imide wherein R₇ is hydrogen,alkyl, phenyl or aralkyl; and --N⁺ R^(a) R^(b) R^(c) or --N(O)R^(a)R^(b) wherein R^(a) to R^(c) are independently alkyl; or aphysiologically acceptable acid addition salt thereof.
 12. A compositionaccording to claim 11, wherein X represents an imidazol-1-yl grouphaving a nitro group in the 2-position or a 1,2,4-triazol-1-yl grouphaving a nitro group in the 3-position.
 13. A composition according toclaim 11, wherein m is
 0. 14. A composition according to claim 11,wherein n is
 1. 15. A composition according to claim 11, wherein each ofR'₁ to R'₅ independently represents hydrogen or C₁ -C₆ alkyl.
 16. Acomposition according to claim 15, wherein R'₁ is hydrogen and each ofR'₂ and R'₅ is independently hydrogen or methyl.
 17. A compositionaccording to claim 11, wherein Z' is a halogen or acyloxy unsubstitutedor substituted by a halogen.
 18. A composition according to claim 11,wherein the compound of formula (A) is present in the form of a saltwith hydrochloric, hydrobromic or hydriodic acid.
 19. A compositionaccording to claim 11, wherein the compound of formula (A) or saltthereof is selected from the group consistingof:1-(2-nitro-1-imidazolyl)-3-(2-acetoxyethylamino)-2-propanol,1-(2-nitro-1-imidazolyl)-3-(2-trifluoroacetoxyethylamino)-2-propanol,1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-chloroethylamino)-2-propanolhydrochloride,1-(3-nitro-1,2,4-triazol-1-yl)-3-(2-bromoethylamino)-2-propanolhydrobromide, and1-(2-nitro-1-imidazolyl)-3-(3-bromopropylamino)-2-propanol hydrobromide.20. A composition according to claim 11, wherein the compound of formula(A) or salt thereof is selected from the group consistingof:1-(2-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride, b1-(2-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanol hydrobromide,1-(2-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanol hydriodide,1-(2-nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanolhydrochloride,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide,1-(2-methyl-4-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide,1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanolhydrochloride,1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-bromoethylamino)-2-propanolhydrobromide,1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-iodoethylamino)-2-propanolhydriodide,1-(2-methyl-5-nitro-1-imidazolyl)-3-(2-fluoroethylamino)-2-propanolhydrochloride,1-(2-nitro-1-imidazolyl)-3-(1-chloro-2-methyl-2-propylamino)-2-propanolhydrochloride,1-(2-nitro-1-imidazolyl)-3-(1-bromo-2-methyl-2-propylamino)-2-propanolhydrobromide,1-(2-nitro-1-imidazolyl)-3-(d1-threo-2-chloro-3-butylamino)-2-propanolhydrochloride,1-(2-nitro-1-imidazolyll)-3-(d1-threo-2-bromo-3-butylamino)-2-propanolhydrobromide,1-(2-nitro-1-imidazolyl)-3-(2-chloro-2,3-dimethyl-3-butylamino)-2-propanolhydrochloride, and1-(2-nitro-1-imidazolyl)-3-(2-bromo-2,3-dimethyl-3-butylamino)-2-propanolhydrobromide.